Method for producing dispersible sterol and stanol compounds

ABSTRACT

A method for preparing sterol/stanol and sterol/stanol ester compositions with improved dispersibility is provided by co-melting the sterol/stanol and/or sterol/stanol ester with highly branched hydrocarbons and then grinding the resulting product. A method for preparing the compounds is also disclosed. The ground compound is suitable for formulating into orally administered products suitable for control of blood serum cholesterol.

FIELD OF THE INVENTION

[0001] The present invention relates to a method of producingsterols/stanols, in particular a method for producing β-sitosterol, withimproved wetting and dispersion properties.

BACKGROUND OF THE INVENTION

[0002] As disclosed in U.S. Pat. Nos. 5,244,877, 5,502,045 and5,578,334, various sterols/stanols, in particular β-sitosterol, areknown to have cholesterol-lowering properties. The consumption ofβ-sitosterol is known to reduce cholesterol levels in the blood stream.Presently due to its handling and storage properties, β-sitosterol isincorporated in foods during its formulation, or while it is beingmanufactured. While this is effective in producing foods with beneficialeffects, the consumer is limited to those foods in which themanufacturers incorporate β-sitosterol.

[0003] It would be highly desirable to provide sterols/stanols in a formthat would be readily dispersible in aqueous media, thus increasing theamount available to micelles in the gut.

[0004] There have been several attempts to provide such a product withlimited success. U.S. Pat. No. 3,881,005 discloses the use of apolyoxyethlene sorbitan monostearate that is added to a sterolsuspension prior to spray drying. U.S. Pat. No. 4,195,084 discloses atall oil suspension suitable for oral administration that is comprisedof finely divided particles of β-sitosterol in water. Other solutionsdescribed in the art include, U.S. Pat. No. 3,004,043 which discloseswater-soluble vegetable oil sterol derivatives and U.S. Pat. No.3,085,939 which discloses oil-in water sterol emulsions. While thesedisclosures provide edible compositions of sterols, the disclosures failto provide the sterol in a form that would be more readily available tothe body.

FIELD OF THE INVENTION

[0005] A primary object of the present invention is to provide orallyadministered self-dispersing solid compositions and methods of producingthese compositions that contain sterols/stanols and hydrocarbons forcontrol of blood serum cholesterol. An orally administeredsterols/stanols and highly branched hydrocarbon solid dosage form isalso claimed. These compositions are provided without the intentionaladdition of water to the composition.

BRIEF DESCRIPTION OF THE FIGURES

[0006]FIG. 1 is a plot of melting point of various β-sitosterol/docusatesodium matrices.

DETAILED DESCRIPTION OF THE INVENTION

[0007] Sterols/stanols are typically derived from agricultural sources,such as corn, soy-based, and pine tree mixtures, and as such arecommonly referred to as sterols. The present invention also contemplatesesters of sterols/stanols through the reaction of the stanol/steol withthe suitable acid. Suitable acids include saturated, unsaturated andpolyunsaturated acids Suitable acids include but not limited to stearic,butyric, lauric, palmitic, oleic, linoleic, linolenic, docohexanoic acidand the like. Suitable methods for preparing these esters are well knownin the art, see for example, U.S. Pat. Nos. 5,502,045, 5,723,747, thecontents of which are incorporated herein by reference. The presentinvention also includes stanols, the reduction product of sterol andhydrogen, this reaction is well known to those with skill in the art.

[0008] The present invention also employs a food grade acceptablehydrocarbon, preferably a branched hydrocarbon. As used throughout thisspecification, food grade acceptable is defined as a material that isappropriate to be incorporated into and consumed in a food by humans.The present invention also includes food grade acceptable salts of thesecompounds.

[0009] As used throughout this invention the hydrocarbon disrupters areunderstood to be a compound which contains primarily carbon and hydrogenatoms and preferably contains at least 3 branched units in the compound.Other atoms including but not limited to oxygen, nitrogen and sulfur mayalso be included in the highly branched hydrocarbon. As used in thisspecification, branched is understood to mean a hydrocarbon chain havinga length of at least two carbon atoms, preferably three or more and morepreferably 4 or more carbon atoms in length that are pendent from themajor backbone of the molecule.

[0010] Among the highly branched hydrocarbons suitable for use in theinvention include docusate sodium; blends of polyglocolized glyceridesconsisting of mono-, di, and tri glycerides and of mono-, and di-fattyesters of polyethylene glycol commercially available as Gelucire 44/14;Gelucire 50/13 (both from Gattefosse Corp.); acetylated monoglycerides,commercially available as Myvacet 600 (Eastman Fine Chemicals); polyoxyl40 hydrogenated caster oil commercially available as Cremopor RH40 (BASFCorp.); polyoxyethylene 20 sorbitan monopalmitate available commerciallyas TWEEN 40; and SPAN 80 (both from ICI Chemicals & Polymers ofAmerica).

[0011] Linear polymeric materials, such as polyethylene glycol,,polyoxyethylene, polyoxypropylene or poloxamer, a nonionicpolyoxyethylene -polyoxypropylene co-polymer commercially available fromBASF Corp., while not branched also produce the disruption effect due tothe variations in chain length present in these materials.

[0012] The hydrocarbon is typically incorporated as a solid at a levelof from about 0.1 to about 50; preferably from about 0.4 to about 10;and most preferably from about 0.5 to about 0.8 weight percent in thesolid.

[0013] The hydrocarbon is added to the sterols/stanols typically byco-melting the materials to a single-phase molten solution result. It isthen preferable to cool and grind the resulting mixture so as to have amore easily handled particle size. Typical particle sizes are from about10 to about 150 microns, preferably from about 25 to about 75 microns.Suitable methods include pulverizing, rotary hammermill, air milling andthe like of which air milling is most preferred. Smaller particles sizesare preferred in that the resulting β-sitosterol product is more readilyexposed to bile salts in the digestive tract.

[0014] A preferred method of determining whether the proper level ofhydrocarbon has been added to the sterol is to employ differentialscanning calorimetry (DSC). This technique measures the heat flow in thesample as a function of temperature. The incorporation of the highlybranched hydrocarbon in the sterols/stanols reduces the crystallinity ofthe solid, which results in improved water dispersibility. When usingDSC, sufficient crystal lattice disruption is known when the heat offusion of the sterol/phytostanol peak drops to less than about 2, andmore preferably less than about 1 Joule/gram, signifying a significantloss of crystal lattice energy. It is this low lattice energy whichcauses a huge increase in wetting ability of sterol/stanol comelts withlattice-disrupting materials claimed in this invention.

[0015] Another technique for measuring the crystallinity of the solidmatrix is to measure the time in which a ground powdered sample of thesolid takes to disperse in unstirred water. When an appropriate amountof the appropriate hydrocarbon material has been added, the solidsolution will disperse in fifty milliliters of water in less than about60 seconds, preferably in less than about 45 seconds and most preferablyless than about 30 seconds. Agitation, including mild agitation such asa stirring bar, can be employed to enhance the dissolution of the solidsolution in water.

[0016] Yet another method to determine whether the desired level ofhydrocarbon has been added to the sterol/stanol, is to measure theturbidity of the solution after 100 milligrams of the groundsterol/stanol/hydrocarbon are added to water. The greater turbidityvalue, the more effectively the solid solution is able to be dispersedin water. Mixtures of sterol/stanol and hydrocarbon with higher turbidtyvalues are believed to provide a more effective in reducing cholesterolwhen consumed. Preferred turbidity levels are greater than about 1500,preferably greater than 2000 and most preferably greater than 3000Nephelometric Turbidity Units (NTU). As used herein turbidity isunderstood to be the same as defined by the United States Pharmacopeia,15^(th) Edition, the light scattering effect of suspended particles andturbidity as the measure of the decrease in the incident beam intensityper unit length of a given suspension. The range of turbidty values isfrom 0 to 20,000 NTU. As a point of reference the turbidity of water iszero. The turbidity of the samples is measured at room temperature.

[0017] Prior to the present invention, sterols were administered as apoorly soluble crystalline solid. The present invention makes possiblethe solid solution delivery of invention for treatment ofhypercholesterolemia. The present invention includes embodiments of oralsolid dosage forms as capsules, including semi-solid fills of thepresent invention in soft capsules or hard-shell gelatin capsules; meltor extruded molded solid tablets; and directly compressed tablets madefrom blends of the sitosterol mixtures with standard tabletingexcipients. In addition, the present invention can be included assemi-solid mixtures for inclusion in foodstuffs. As used in thisinvention, semi-solid is understood to mean highly viscous materialsthat do not flow easily. Generally semi-solid materials have a viscosityof greater than about 5,000 centipoise, more typically greater thanabout 10,000 centipoise.

[0018] A principal advantage of the present invention is the productionof sterol/stanol with improved dispersibility that minimizes theincorporation of additional ingredients, i.e. surfactants, dispersants,etc. Furthermore, since the hydrocarbon is added to the sterol/stanol asa solid, and without the addition of water to form an emulsion,suspension and the like, an expensive drying step is not required.

[0019] The present invention can also incorporate additional ingredientscommonly used for making a tablet. Among these items are excipientswhich is understood to mean substance and materials used in the drug orfood industry which do not alter the character and function of theactive components of the aggregate. Flavors which may be optionallyadded are well known to those in the art, including synthetic flavoroils, and/or oils from plants, leaves flowers, fruits and so forth, andcombinations thereof. Representative flavor oils include spearmint,peppermint, cinnamon, wintergreen, citrus oils, and fruit oils. Othersuitable flavors include caramel, bubble gum and the like. Flavoringsare typically employed at levels of from about 1 to about 5 weightpercent.

[0020] Sweetening agents may also be employed such as monosaccharides,disaccharides, and polysaccharides such as xylose, ribose, glucose,mannose, galactose, fructose, dextrose, sucrose, maltose, corn syrup andthe like. Artificial agents may also be employed including saccharin,cyclamates and acesulfam-K, aspartame, and the like. Sweeteners aretypically employed at levels of from about 1 to about 5 weight percent.

[0021] Dispersal agents include hydroxymethyl cellulose, corn starch,croscarmellose cellulose (Ac-Di-Sol made by FMC Corp.) and mixturesthereof. Dispersal agents may be incorporated from about 2 to about 20weight percent.

[0022] Lubricants can also be added to the mixture to aid in theprocessing of the tablets. These compounds are well known in the art,with magnesium stearate being most preferred. Lubricants are typicallyemployed at levels of from about 1 to about 5 weight percent.

[0023] After the invention is ground to a powder it is packaged in anysuitable size as may be required. The form the invention is contained inmay also vary depending on the preference of the consumer. Suitableforms include tablets, chewable dosages or applied to beverages andfoodstuffs. In a preferred embodiment, the invention may be packaged insingle serving size packets containing from about 5 to about 50 gramsper packet.

[0024] The invention will now be illustrated by, but is not intended tobe limited to, the following examples. In these examples it isunderstood that unless noted otherwise, all parts are weight percent.

EXAMPLE 1

[0025] Sterols (Generol 122 available from Henkel Corp.) and 20%docusate sodium U.S.P. were melted at 150° C. The mixture was cooled toambient temperature, approximately 23° C. and first coarsely choppedthen milled under liquid nitrogen to a powder of approximately 40 micronmean diameter.

EXAMPLE 2

[0026] The powder of Example 1 was added to approximately 50 millilitersof water and was found to spontaneously wet and disperse withoutstirring.

EXAMPLE 3

[0027] A docusate sodium/β-sitosterol matrix was prepared. The samplewas shaken for 30 seconds in a vial containing 25 milliliter deionizedwater. In Series 1, turbidity measurements were taken after allowing theshaken sample to stand one minute. In Series 2, measurements were madeafter standing for 20 minutes. The results are provided in the followingtable. % Docusate sodium Series 1 (NTU) Series 2 (NTU) 10 (1^(st) batch)600 386 10 (2^(nd) batch) 538 231 1 921 700 0.8 2136 1777 0.5 1841 15730.1 714 307 100% sterol 1301 523 100% docusate 1.22 0.441 sodiumDeionized water 0.85 0.6

[0028] The 100% sterol, 100% docusate sodium and water were employed ascontrols. This example demonstrates an optimal range of about 0.5 toabout 0.8 weight percent sodium docusate incorporated in the sterolmaterial for purposes of providing a dispersible sterol material.

EXAMPLE 4

[0029] A 500 milligram sample of a 99:1 sitosterol/docusate sodiummatrix was placed in 200 milliliters of unstirred tap water at ambienttemperature resulted in the sample dispersing into the water in 25seconds.

EXAMPLE 5

[0030] Additional sitosterol/docusate sodium matrices were prepared andadded to water. The mixtures demonstrated enhanced wetting as reportedin the table below. Time (seconds) to disperse Percent docusate sodium200 mg of Sample in 250 ml In Matrix Unstirred Water 20 97 10 8 1.0 70.8 11 0.5 45

[0031] By comparison, a 100% sitosterol powder sample under similarconditions does not wet at all, samples left for a long as three dayswith vigorous stirring immediately floated to the top of the water whenagitation was stopped.

[0032] The above results depict a range of docusate sodium whichprovides a range of values with high degree of dispersibility in water.

EXAMPLE 6

[0033] Docusate sodium was used as the lattice disrupting material andwas co-melted and recongealed with β-sitosterol. Differential scanningcalorimetry (DSC) was used to measure the heat flow as a function oftemperature. The results are provided in FIG. 1. As measured using DSCsufficient disruption of the crystal lattice occurs when the heat offusion of the β-sitosterol peak drop to less than about 1 Joule/gram.

What is claimed is:
 1. A solid composition suitable to be orallyadministered comprising a sterol/stanol or sterol/stanol estercomposition in an amount sufficient to lower serum cholesterol and aneffective amount of a hydrocarbon to provide a water dispersiblemixture, wherein the composition is prepared without the intentionaladdition of water.
 2. The composition of claim 1 wherein sterol/stanolor sterol/stanol ester is present in the amount from about 50 to about99.9 weight percent.
 3. The composition of claim 1 wherein thehydrocarbon is selected from the group consisting of docusate sodium,;mono, di and tri glycerides, polyglocolized glycerides, mono-, and di-fatty esters of polyethylene; acetylated monoglycerides; polyoxyl 40hydrogenated castor oil; and polyoxyethylene 20 sorbitan monopalmitate.4. The composition of claim 1 wherein the hydrocarbon is a linearpolymer selected from the group consisting of polyethylene glycol,polyoxyethylene, polyoxypropylene and polyoxyethylene/polyoxypropyleneco-polymers.
 5. A method of producing a water-dispersible dosage form tobe orally administered containing a sterol/stanol or sterol/stanol estercomprising: a) providing a sterol/stanol or sterol/stanol ester in anamount sufficient to reduce serum cholesterol; b) providing ahydrocarbon in an amount sufficient to provide a water dispersible form;c)admixing the sterol/stanol or sterol/stanol ester and the hydrocarbonin the absence of water.
 7. The method of claim 6 wherein the mixture isground to a particle size of from about 25 to about 75 microns.
 8. Themethod of claim of claim 6 wherein the hydrocarbon is selected from thegroup consisting of docusate sodium,; mono, di and tri glycerides,polyglocolized glycerides mono-, and di-fatty esters of polyethylene;acetylated monoglycerides; polyoxyl 40 hydrogenated caster oil;polyoxyethylene 20 sorbitan monopalmitate, polyethylene glycol,polyoxyethylene, polyoxypropylene and polyoxyethylene/polyoxypropyleneco-polymers.
 9. The method of claim 6 wherein the mixture is compressedto form a tablet.
 10. The method of claim 6 wherein the mixture isheated while being mixed.
 11. The method of claim 10 wherein the mixtureis heated to create a molten mixture.